Many systemic autoimmune diseases are more common in females than in males. This is particularly evident in Sjvgren's Syndrome, systemic lupus erythromatosis (SLE) and thyroid autoimmunity, where the ratio of females to males ranges from 20:1 to 8:1. Our current understanding of the etiology of SLE implies important roles for genetics and environmental factors such as sex hormones. Analyses of mouse models of SLE have proven good models for both;however, the relative importance of genes versus sex hormones is still largely unknown. Using a mouse model system of SLE, in which we can segregate the effects of genes and hormones on the immune system in vivo we have found that even before puberty female bone marrow cells express an intrinsic capacity to drive accelerated lupus-like disease development in a hormone independent manner. The focus of the proposed studies aims at investigating if the different capacity to transfer lupus-like disease is an intrinsic sex-specific, sex-hormone independent property of the developing immune system (aim 1). We will do so by investigating disease development patterns in fetal liver chimera mice, including analyses of the immune system phenotype and end-organ, i.e. kidney, involvement (aim 1.1), and by analyzing properties of immune cells after transfer into recipient mice with controlled levels of circulating sex hormones (aim 1.2). Secondly, we wish to identify which cell population(s) is required and necessary for the transfer of accelerated lupus-like disease development in female-to-male BWF1 bone marrow chimeras (aim 2). To do so, we will target immune cells of a given sex with green fluorescent proteins prior to transfer into sex-matched or mismatched lethally irradiated recipients. In addition, we will create mixed BM chimeras, allowing us to investigate male and female immune cells in the same in vivo environment. The nature of the proposed studies is innovative and or high impact as this, to our knowledge;represent the first model in which the effect of genes and sex hormones can be independently investigated. Results obtained from these studies may help our understanding of why females are more prone to autoimmunity in general and SLE in particular and offers potential new screening and early treatment strategies for girls with a genetic predisposition to autoimmunity. PUBLIC HEALTH RELEVANCE: Women are much more prone to develop autoimmune diseases such as Sjvgren's Syndrome, systemic lupus erythromatosis (SLE) and thyroid autoimmunity (Hashimoto's disease and Graves'disease). Although much effort has been put forward, we still do not know the relative importance of genetics and sex hormonal exposure. Investigations of the young immune system, even prior to birth, may reveal sex-specific differences yet unknown and involved in disease development. Such knowledge may provide us with an understanding of whether genes or the production of sex hormones are the main driving force for autoimmune disease development and may significantly alter our way of screening and treating young girls and women with a predisposition for these diseases.